The transmissible spongiform encephalopathies (TSEs) comprise a group of neurodegenerative diseases affecting both humans and animals. The TSEs are remarkable in that they appear to be caused by a host-encoded protein (the prion protein) that becomes modified in an as yet unknown way that reduces the host's capability to completely degrade the peptide and it accumulates as amyloid in the brain. Also, inherited forms of these diseases in humans have been associated with gene mutations causing changes in the primary amino acid sequence of the protein. Up to this point' there is considerable similarity between TSEs and AIzheimer's disease. However, most occurrences of TSEs are not inherited, but rather acquired by an apparent infectious process. Moreover, it is the protein itself that appears to be the transmissible agent. Research in this field is now focused on three main issues, (1)What is the nature of the posttranslational change that modifies the protein?, (2) By what mechanism does the modified protein convert its normal counterpart?, and ( 3) How can these changes account for distinct strains of these transmissible proteinaceous agents? This grant application proposes to continue studies on the physicochemical and biological properties of distinct strains of the transmissible mink encephalopathy (TME) agent. These hamster models of TME are unique in that they represent the first identification of individual strains of agent having distinct clinical and biological features, as well as producing prion proteins having different biochemical and physical properties. Because these diseases are produced in a single outbred species, differences in the disease-specific prion proteins (PrPTME) cannot be due to changes in primary amino acid sequence, but must be conveyed by properties of the proteins themselves. These observations emphasize the importance of the transmissible agent in determining the outcome of infection, independent of the PrP genotype of the host. This application proposes to examine the secondary structure of PrPTME by Fourier transform infrared spectroscopy. to study the biologic behavior of TME strains in various species of hamsters and in transgenic mice expressing the hamster prion protein gene, and to attempt to study the biosynthesis and degradation of PrPTME in infected brain slices. The results of these studies will be relevant to not only our understanding of the pathogenesis of TSEs, but also to other neurodegenerative disorders and may provide new insights into protein-protein interactions.